Diketones and their use

ABSTRACT

IN WHICH R1, R2, R3 and Z indicate groups or atoms as indicated above.   OR A TAUTOMERIC FORM THEREOF IN WHICH R1 and R2 represent hydrogen or lower hydrocarbyl groups with the proviso that the number of carbon atoms of R1 and R2 taken together is from 1-4 R3 represents a hydrogen, acyl or alkyl group containing 1-24 carbon atoms R4 represents an alcohol protecting group resistant to alkali but removable under acid reaction conditions Z represents an oxygen or sulphur atom are claimed and a process for subjecting these diketones to ring closure conditions as to form a 2,3-dihydrofuran-3-one of the following structure   Novel diketones of the structure

States Patent [1 1 van den Ouweland DIKETONES AND THEIR USE [75]Inventor: Godefridus Antonius Maria van den Ouweland, Zevenaar,Netherlands [73] Assignee: Lever Brothers Company, New

York, NY.

[22] Filed: Dec. 13, 1971 [21] Appl. No.: 207,631

[30] Foreign Application Priority Data Dec. 21, 1970 Great Britain60562/70 [56] References Cited UNITED STATES PATENTS 3,694,466 9/1972Buchi et al 260/347.8

Primary ExaminerJohn D. Randolph Assistant ExaminerBernard DentzAttorney, Agent, or F irm-Lever Brothers Company [57] ABSTRACT Noveldiketones of the structure or a tautomeric form thereof in which R and Rrepresent hydrogen or lower hydrocarbyl groups with the proviso that thenumber of carbon atoms of R and R taken together is from 1-4 Rrepresents a hydrogen, acyl or alkyl group' containing l-24 carbon atomsR represents an alcohol protecting group resistant to alkali butremovable under acid reaction conditions I. Z represents an oxygen orsulphur atom are claimed and a process for subjecting these diketones toring closure conditions as to form a 2,3-dihydrofuran-3-one of thefollowing structure in which R, R R and Z indicate groups or atoms asindicated above.

7 Claims, No Drawings DIKETONES-AND THEIR use BACKGROUND OF THEINVENTION 1. Field of the Invention The invention relates to thepreparation of certain furan derivatives, in particular of certainsubstituted, 2,3-dihydrofuran-3-ones. More in particular the inventionrelates to the synthesis of compounds of the general formula:

Compounds satisfying this general formula are important flavouringagents or precursors therefor, which contribute to e.g. fruity and meatyflavours, dependent e.g. on their nature and concentration.

2. The Prior Art Although diverse synthetic routes forseveral members ofthe groups of compounds satisfying the general formula have beensuggested, none of these routes has been considered satisfactory forvarious reasons. Very frequently these syntheses employed relativelyexpensive starting materials or starting-materials thatare accessibleonly with difficulty, such as certain carbohydrates and derivativesthereof, and often reaction mixtures were obtained which containedappreciable amounts of undesirable byproducts which were difficult toremove, so that, consequently, the desired dihydrofuranone was onlyobtained in a relatively low yield.

SUMMARY OF THE INVENTION DESCRIPTION OF THE INVENTION According to theinvention the desired dihydrofura- I none is prepared by ring closureofa novel diketone of the general formula:

in'which R and- R represent a hydrogen atom or a lower aliphatichydrocarbyl group preferably each an alkyl group in such a way that thenumber of carbon atoms of R and R taken togetherjs between 1 and 4,whereas R represents hydrogen or a lower acyl or alkyl group, containingl24, preferably 1-8, carbon atoms, more in particular an alkyl groupcontaining 1-4 carbon atoms, Z represents an oxygen or a sulphur atom, Rrepresents such a group that --OR constitutes an alcohol protectivegroup, which is resistant to alkali but which can be removed under acidconditions so that R preferably represents a C,C alkyl group, as e.g.derived from methanol, ethanol, butanol, isoprop'anol, isobutanol,isopentanol, triphenyl carbinol, tertiary butanol, tertiary pentanol,tertiary hexanol and higher homologues thereof, or OR may represent amixed acetal group, such as a tetrahydrofuranyl group, atetrahydropyranyl group an alpha-substituted methyl-ethyl ether or analphaor beta-unsaturated ether group, such as an allyl ether group,benzyl ether group or a metaor para-methoxy phenyl group.

Diketones of the structure indicated above may show keto-enoltautomerism and may occur in an enol form and the invention alsocomprises subjecting these compounds to ring closure. There are e.g.experimental indications that the keto-enol tautomerism equilibrium ismore shifted towards one of the enols under specific conditions.

and the invention thus alsocomprises subjecting these enol forms ormixtures to ring closure in such a way that the desired compound isformed.

The ring closure reaction can be carried out in a wide range of solventssuch as water, organic solvents as e.g. hydrocarbons, halogenatedhydrocarbons, carboxylic acids, ethers or alcohols dependent on the ringclosure catalyst used. Preferred solvents are tetrachloromethane,dichloromethane, diethyl ether, tetrahydrofuran, dioxane, benzene,toluene, pentane, water, methanol, ethanol, butanol or chloroform.

The ring closure reaction is usually carried out in the presence of aring closure catalyst e.g. a lower aliphatic monoor polycarboxylic acidcontaining up to 8, preferably 4 carbon atoms; an acid reacting ionexchange resin, an inorganic acid and acids in general according to thedefinition of G. N. Lewis, including aprotic acids, may also be used.Acetic acid, oxalic acid, citric acid, chloroacetic acid, hydrochloricacid, sulphuric acid, borontrifluoride, zinc chloride and stannouschloride ,are preferred ring closure catalysts. Some of the sol- "Theamount of ring closure catalyst employed may vary widely dependent onthe nature of the catalyst and the prevailing reaction conditions. Insome cases catalytic amounts of 0.01% w.w. calculated on diketone may besufficient (e.g. hydrochloric acid) and in other cases an equimolarquantity may be desirable (lower aliphatic (thio) carboxylic acids). Ingeneral 0.001% w.w. several times w.w. calculated on the diketone ofcatalyst can be used.

The ring closure may conveniently be effected in 0.5N aqueoushydrochloric acid at reflux temperature and the reaction may take 30min. In general reaction temperatures may vary from 30 to 150C, alsodependent on whether the free hydroxy compound or an ester is aimed at,and the reaction time from several, say 2 minutes to a few, say 6 hours;a time of 10-40 minutes at reflux temperature is preferred. The reac-'tion product comprises the 4-hydroxy or 4-thiol compound together withits ester or ether. Further reaction with the acid may cause morecomplete saponification. Usually the reaction is carried out atatmospheric pressure but subor superatmospheric pressures may beemployed.

. rated in such foodstuffs during their manufacture.

The diketone derivatives of the general formula mentioned above areconveniently prepared from certain halogeno compounds by reacting themwith carboxylate or thiocarboxylate ions derived from (thio) carboxylicacids of the structure R Zl-I, in which R represents an acyl group asdefined above. The carboxylate ions are conveniently obtained bydissolving the salts, in particular the alkali salts of the acidsconcerned in the appropriate solvent. Usually the carboxylate is used in0.5- molar quantities calculated on the halogen compound, preferablybetween 1 and 2 molar quantities.

Halogeno compounds which are conveniently converted may have thefollowing general formula, but other stereoisomeric or tautomeric formsthereof may also be converted.

' Advances in Organic Chemistry", vol. 5, pp. l-46,

1965, by A. J. Parker.

The reaction temperature and time can widely, usually above 0C, andrange normally from 100C and from 10 minutes to a few hours. In thesubstitution of X by SR as well as in the cyclization reaction the samesolvent is used as in the preparation of the halogeno compound, whichavoids the need to be varied remove the solvent between the differentreaction steps.

Consequently, it is an object of the invention to treat the halogenocompound with a free thiocarboxylic acid as e.g. thioacetic acid, inwhich process several reaction steps are carried out in one operation(one vessel reaction). The amount of free thioacid used is usually 'amolar excess calculated on the halogeno compound;

generally vup to 50 molar percent excess is beneficial. Larger amounts,although their use has no advantages, may however also be employed. Itis preferred to add the thioacid dropwise to the dissolved halogenocompound.

The halogeno compound is in turn conveniently prepared by reacting acompound of the general formula, (but other stereoisomeric or tautomericforms thereof may also be converted) with free halogen,

tit

as e.g. bubbling chlorine or bromine through a solution of the compound,or a halogenating agent as e.g. N- bromoor chlorosuccinimide or thecorresponding phthalimides.

The introduction of the halogenato m is preferably carried out in. aninert solvent like hydrocarbons, such as cyclohexane, benzene;halogenated hydrocarbons, such as chloroform, tetrachloromethane',furthermore in'acetonitrile, nitromethane, dimethylformamide,dimethylsulphoxide. The reaction temperature during thehalogenationusually is above -30C, preferably be- .tween 0 and 100C incase free halogen is used, preferably from 30 to +10C; with the imidesbetween 20 and C. In general, to avoid the introduction of more thanonehalogen atom, no more than molar quantities of halogen are introducedinto the reaction mixture. It

is not necessary to purify the reaction mixture containing the halogenocompound, but usually it is desirable, in connection with the reactionwith the carboxylate ion, to replace the solvent in which it isdissolved, by a dipolar aprotic solvent, which in some cases may beeffected by addition of such a less volatile dipolar aprotic solvent andevaporating off the more volatile first solvent, occurring in theoriginal reaction mixture.

in which Et represents an ethyl group or another lower alkyl group. Thereaction is catalyzed by bases and in order to avoid polymerization ofthe starting material it is preferred that R represents an alkyl grouprather than a hydrogen atom, so that acetone or a higher alkylmethylketone is coupled with analpha-hydroxy carboxylic acid ester, with aprotected hydroxyl group, e.g. an ether group.

The non-halogenated compounds of the general formula mentioned above, inwhich R represents hydrogen, are conveniently prepared via anotherroute, viz. by coupling The following examples illustrate the invention.

EXAMPLE 1 Preparation of 4-thioacetoxy-2,S-dimethyl-2,3-dihydrofuran-3-one To a suspension of 27.0 g (0.5 moles)of sodium methoxide in 250 ml of dry ether was added and in the courseof 1 hour a mixture of 29.0 g (0.5 moles) of acetone and 50.5 g (0.25moles) of pyranylether of ethyllactate (b.p. 63C at 0.1 mm Hg), preparedfrom ethyllactate and dihydropyran according to the procedure describedby D. N. Robertson .l.Org.Chem., 25, 931 1960).

During the addition the temperature of the mixture raised to refluxtemperature (35) and the colour of the mixture turned to a reddishbrown. Stirring was continued after completing the addition for another20 min- Infrared absorption characteristics: maxima at (in utes in orderto complete the formation of 2-tetra- 1 in 80 ml of drytetra-chloromethane was chilled in an ice-bath to approximately 10C.Then in 30 minutes, 7.1 g (0.1 mole) of chlorine was introduced into thereaction mixture and stirring'was continued for another 30 minutes tocomplete the formation of 4-chloro-2-tetrahydropyranyloxy-3,5-hexanedione, which structure was confirmed bynuclear magnetic resonance in- 1 frared and mass-spectroscopy.

(broad, weak), 1452, 1440, 1355, 1200, 1125, 1075, 1032, 966, 871 cm.

The mass-spectrum showed peaks with decreasing intensity by m/e 85, 43,41, 57, 55, 67, 86,56,119, 92. NMR data (solution in CCl, withtrimethylsilane as an internal standard) 6 p.p.m. gougiet H 5= p.p.m. ouet a=1.40 p.p.m; doublet hldlcatmg-m- H;C( J- 6=1.46 p.p.m. doublet5=1.60 p.p.m. broad singlet Indicating 8=2.34 p.p.m. singlet I a=2.31p.p.m. singlet; .i O

a=3.1-4.0 p.p.m. multiplet Indicating".-. X 0 If} H 6=4.24 p p m quartetO 6=4.20p pm quartet; H C A:

l I g 5=4.54.8p.p.m.rnu1tip1et Indicating (I) H U 6:2.82 p.p.m. singdeg1 p.p.m.s1ng e 5=,5.25 p.p.m. singlet C-JJC- 5=5.32 p.p.m. singlet 11 l1% To-the reaction mixture were then added dropwise,

, with stirring and cooling to approximately 15C, 9.12

g (0.12 moles) of thioacetic acid. Upon completion of addition thereaction mixture was stirred overnight at room temperature and filtered,and the filtrate was taken up in ether, washed, dried and evaporated.Distillation of the residue yielded 1 1.2 g calculated on2-tetrahydropyranyloxy-3,S-hexanedione) of 4- thioacetoxy2,5-dimethyl-2,3-dihydrofuran-3-one with b.p. 63-65C/0.05 mm Hg, m,1.5297.

Infrared absorption characteristicsz'maxima at (in CCl,): 2990, 2930,1720 (shoulder), 1705, 1590, 1440,

1035, 985, 947, 615,- 605, cm". Mass data m/e 186(mo1.ion),144,115,111,102, 101, 71, 43.

N.M.R. in cm,

2.32 ppm 4.51 ppm lzXAM l'Ll'. 2

I Preparation of 4-thlnacetoxy-5-m ethyl-2,3-dihydrofuran-3-one To asuspension of 27.0 g (0.5 moles) of sodium methoxide in 250 m1 of dryether were added with stirring 72 g (0.33 mole) of the pyranyl ether ofn-butyl glycolate (b.p.- 80C at 0.1 mm Hg, n 1.4.438). Acetone (29 g,0.5 mole) was then added dropwise to the mixture at'such a rate as tomaintain the temperature at gentle reflux. Finally a light tan solutionwas obtained after completion of the addition. The solution was stirredfor another 15 minutes at 30-35C and poured out onto a mixture of 60 gof concentrated hy- -drochloric acid and 300 g of ice. The ether layerwas above-prepared pentanedione and 48 g (0.6 mol) of .pyridine in 160ml of dry tetrachlorom'ethane at l-l C was introduced in the course of30 min: 14.2 g (0.2 mol) of chlorine. The formation of the corresponding4-chloro compound was established by infrared and mass spectrometry asfollows:

lnfrared adsorption characteristics: maxima at (in .CCl 2940, 28.70,2850, 1720 (broad), 1605 (broad),

The mass spectrum showed peaks with decreasing intensities at m/e: 85,43, 41, 57, 55,67, 101, 56, 86, 84. After an additional stirring periodof 1 hour, 18.24 g (0.24 mol) of thioacetic acid was added during minwhile the temperature of the reaction mixture was kept below C by meansof an ice-bath. After standing overnight at room temperature thereaction mixture was filtered and the filtrate diluted with 500 ml ofether. The ethereal solution was washed and dried, and solvent wasremoved at 35C under reduced pressure. To complete the cyclization ofthe crude l-tetrahydropyranyloxy-3-thioacetoxy-2,4-pentanedione theresidue was dissolved in 200 ml of methanol and refluxed with 0.5 g ofp-toluenesulfonicacid for one hour. After working up the reactionmixture, the product was elution with light petroleum ether (3:1).lnfrared absorption characteristics of the title compound are maxima at(in CC1,): 2940, 1720 (broad), 1597, 1420,

1387,1350,1337,1293,1l53,11l0,1015, 945, 914, 686, 633, 620, 605 cm".Mass data m/e 172 (mol.ion), 130, 101, 88, 87, 85, 71, 45, 43, 42.

8 2.28 ppm broadened singlet (indicating Cl-1 on 5 -position) NMR inCDCl 5 2.40 ppm singlet (indicating CH of acetyl group) I 8 4.68 ppmbroadened singlet (indicating protons on 2-position I (Trimethylsilaneas an internal standard) I isolated by columnchromatography oversilicagel and 8 EXAMPLE 3 Preparation of 4-hydroxy-2,5-dimethyl-2,3-dihydrofuran-3-onc To a solution of 21.4 g (0.1 mole) of Ltetrahydropyranyloxy-3,S-hexanedione (obtained as described inExample 1) in ml of dry tetrachloromethane was added 17.8 g (0.1 mole)of N- bromosuccinimide; after a few seconds the exothermic reactionstarted and the temperature of the reaction rose to 76C. Stirring wascontinued for another 15 minutes and the reaction mixture was cooled andfiltered, and the filtrate evaporated in a water-jet vacuum at roomtemperature. The 4-bromo-2- tetrahydropyranyl oxy -3,5-hexanedion e thusobtained was identified by infrared, N MR and mass spectrometry asfollows:

Infrared adsorption characteristics: maxima at (in CC1 2940, 2850, 1747,1718 (broad), 1452, 1440, 1354, 1200, 1123, 1074, 1033, 972, 870 cm.Mass spectral data: peaks at m/e 85, 43, 41, 57, 55, 67, 86, 45, 71,129. NMR (CCI, solution with trimethylsilane as internal standard)a=2.32 p.p.rn. singlet n} O 5=2.45 ppm. singlet IL HaCL 6:3.1-41] p.p.m.multiplet 0 The evaporated filtrate was used in the next step withoutfurther purification and dissolved in 100 ml of dimethylformamide. 19.6g (0.2 mole) of potassium acetate were then added to the solution andthe mixture was stirred for 30 minutes at 35?40C. After this stirringperiod the mixture was filtered and the filtrate concentrated underreduced pressure. 4'-acetoxy-2- tetrahydropyranyloxy-3,S-hexanedioncould be isolated by short path distillation (b.p. ll6-l18C/0.1 mm Hg).The infrared spectrum of the liquid substance shows absorption peaks at2940, 2870, 1756, 1740, 1725, l440,1370,1230,1l26,1075,l033, 976, 901,871, 615 cm. The mass spectrum shows peaks with decreasing intensitiesat m/e 85, 43, 116, 57, 41, 55,

The 4-acetoxy-2-tetrahydropyranyloxy-3,5- hexanedione was dissolved in200 ml of a 0.5N HCl solut-ion and refluxed for 1 hour, cooled to 30Cand continuously extracted with ether for 18 hours. The ether 74, 129,67, 200. NMR spectrum (trimeth lsil d extract was dried and evaporatedand the residue was as i t al t d rd i CC! l ti crystallised fromether-light petroleum. After standing overnight in the refrigerator thecrystals were collected by filtration (3.8 g, 30% yield calculated on 2-O tetrahydropyranyloxy-3,5-hexanedi0ne), mp. a=1.2s .d b1 na=1.33g.g.:.d b1 t ..}H3C(l1 78 80C, and proved to be GLC pure4-hyclroxy-2,5-

dimethyl-2,3-dihydrofuran-3-one.

6=1.59 p.p.m. broad singlet O EXAMPLES 4 9 EA Effect of solvents on thepreparation of 4-hydroxy-2,5-dimethyl-2,3-dihydrofuranone and the Hcorresponding 4-acetoxy compound H H The process as described in Example3 was repeated, now using, however, different solvents for the reactionO 0 c s=z oop p m.singlet g with potassium acetate and the subsequentsubstrtu 6=2.16 p.p.m.sing1et HaC-C-O and HaC C tron. Evaporatmg'off thetetrachloromethane from the i brominated product was conducted and 100ml of a di- 6:3.140 Pam broad Singlet O polar aprotrc solvent wasintroduced. After which the A various operations described in theprevious example 0 were carried out with some modifications in thereaction time as indicated below. The yields of 4-hydroxy-2,5-dimethyl-2,3-dihydrofuran- 3-one (2,5-

dimethylfurenidone) and the corresponding4-acetoxy 5:428 multlpletcompound in the reaction mixture were determined by H3C+ agaschromatographic method using ntetradecanol as E an internal standard.The results are tabulated below:

Ex. Solvent Reaction Yield calculated on starting 0 time temp. diketone(percentage of theory) 4-hydroxy 4-acetoxy furenidone furenidone 4Acetone 7 h 56C 27 3 (reflux) 5 Acetoni- 10 min. 2) l trile 82C 6Dimethyl 45 min. 20C 24 3 sulfoxide 7 NN-dimethyl-, 30 min. 45C 30 lformamide, 8 Acetic min, 80C 39 l acid 9 Methanol 30 min. 68C 16 46:4.58 p.p.m. broad singlet O/H EXAMPLES 0-21 r Effect of variation inthe ring closure conditions in the 0 preparation of 4hydroxy-2,5-dimethyl-2,3-dihydrofuran-3-one and the corresponding4-acetoxy compound 4-acetoxy-2-tetrahydropyranyloxy-3,5-hexanedionewasprepared as described in Example 3 and ring closure reaction ofasample was subsequently carried out under various conditions astabulated below. The yields of the 4-hydroxy and 4-acetoxy furenidoneswere determined as described in Examples 4-9, calculated as a percentagebased on the starting diketone.

Reaction Yield of Ex. Ring'closure catalyst and time temp. 4-hydroxy-4-acetoxysolvent furenidone furenidone I0 20 voLpts N HCl 20 h 20C 42 1ll 20 vol.pts 0.025 N HCl 92 h 20C 22 10 12 20 vol.pts 0.05 N HCl 30min. 100C 26 14 1.3 20 voLpts 0.25 N HCl 45 min. C 35 v 4 14 20 vol.pts0.5 N HCl 30 min. C 23 l-2 15 20 vn|.pts 3 N HCl 30 min. 100C 9 0 16 20vol.pts H O 0.5% w.w, I

acetic acid 5% h 100C 30 9 Reaction Yield of Ex, Ring closure catalystand time temp. 4-hydroxy- 4-acetoxysolvent furenidone furenidone 17 30vol.pts H,() 2 pts ion exchange resin Biorad Biorad AG-50W-X8 20 min.100C 32 5 l8 l0 voLpts diethylether 0.1 pt BFa-ZCgHSOCgH; min. C 0 l2 I920 vol.pts benzene 0.1 pt

BF,,3.2C,H,OC H, 10 min. 80C 6-7 19 .20 r 20 voLpts benzene 0.1%

w.w. paratoluene sulphonic acid l h 80C 0 21 10 voLpts chloroform I 0.1%w.w. dry hydrochloric acid 10 min. 20C 38 5 EXAMPLES 22-27 Quantity ofCarboxy lute used Ex. Yield of 4- carboxylate hydroxy'furenidone 4 2 eqPotassium acetate 27% g 22 1 eq I Potassium acetate 24% 23 '5 eqPotassium acetate 26% 24 2 eq Potassium formate 15% 25 2 eq Sodiumacetate 46% 26 2 eq Barium acetate 13% 27 2 eq Potassium carbonate 5%Similar results could be obtained with potassium butyrntc or hexanoate.

EXAMPLE 2:;

Preparation of 4-hydroxy5-methyl-2,3-dihydrofuran'3-one To a solution of20 g (0.1 mol) of tetrahydropyranyloxy-Z,4-pentanedione (prepared asdescribed above) in 100 ml of dry tetrachloromethane was added 17.8 g(0.1 mol) of N-bromosuccinimide and the mixture was stirred for 10minutes at 70C. Then the reaction mixture was filtered and the solventremoved from the filtrate by evaporation in a water-jet vacuum. The massspectrum of the 3-bromo-ltetrahydropyranyloxy-2,4-pentanedione showedpeaks with decreasing intensities at m/e 85, 43, 41, 57, 55, 56, 67,101,86,.84.

Infrared absorption characteristics; maxima at (in CCl 2940, 2870,2850,1746, 1718 (broad), 1600 (broad, weak), 1440,1353, 1200, 1129,1074,1035, 960, 904, 869 cm.

The above-described b'romo derivative was dissolved in 200 ml ofacetone, to this solution 19.6 g (0.2 mol) of potassiumacetate was addedand the mixture was stirred for 10 minutes at 55-58C. After thisstirring period the mixture was filtered and the filtrate dried byEXAMPLE 29 Preparation of4-thioacetoxy-2-methyl-S-ethyl-2,3-dihydrofuran- 3-one According to theprocedure described in Example 1, a quantity of 96 g (42%) ofZ-tetrahydropyranyloxy- 3,5-heptanedione; b.p. 83C/0.02 mm Hg, n 1.4754was preparedfrom 202 g of pyranylether of ethyl lactate and 144 g ofbutane-Z-one.

into a stirred solution of 11.4 g (0.05 mol) of 2-tetrahydropyranyloxy-3,S-heptanedione and 12.0 g (0.15 mol) of pyridinein 40 ml of dry tetrachloromethane was introduced 3.6 g (0.05 mol ofchlorine at 10C.

The mass spectrum of the so obtained 4-chlor0-2-tetrahydropyranyloxy-3,S-heptanedione showed peaks at m/e 85, 43, 41,57, 55, 67, 45,86, 84, S6.

Infrared absorption characteristics (in CCl 2940, 2870, 2850, 1725(broad), 1590 (broad) 1450, 1440, 1199, 1120, 1073, 1031, 1020, 972,890, 870 cm.

5 0 NM R in G014. Trimethylsilane as internal standard:

15=1.03 p.p.m. triplet CH3CH2 s=1.17 p.p.m. doublet 5=1.27 p. 6=1.36p.5=1.41p.

S=2.64 p.p.m. quartet I (I) CHa-CHr 5=3.14.0p.p.m.multiplet O 1 6=4.04.5p.p.m. multiplet 6=4.54.8 p.p.m. multiplet 0 To the reaction mixturecontaining the chloro compound was then added under-stirring and cooling4.56

g (0.06 mol) of thioacetic acid. Upon completion of the addition thereaction mixture was stirred for another hour at room temperature,filtered and worked up as described above. Distillation of the residueyielded 3.95 40% I of thioacetoxy-2-methyl-5ethyl-2,3-dihydrofuran-3-one with b.p. 82C/ 0.1 mm Hg, n 1.5168.

Nuclear magnetic resonance date (CCl solution trimethyl silane asinternal standard 8 1.21 ppm triplet C iCH 1.46 ppm doublet CH on2-position 2.35 ppm singlet CHgfrom acetyl group 2.59 ppm quartet CH4.62 ppm quartet H on 2-position Infrared absorption characteristicsmaxima at (in CC1 2983, 2942, 2935, 2880, 1710, 1675, 1581, 1462, 1448,1441, 1430, 1387, 1369, 1360, 1352, 1312, 1280, 1246, 1198, 1160, 1130,1108, 1085, 1060, 1040, 1016, 947, 912, 862, 655, 611, 546, 516, 467,412CM-l. Mass spectral data EXAMPLE Preparation of a mixture of4-acetoxy-2-methyl-5-ethyl-2,3-dihydrofuran-3-one,4-hydroxy-2-methyl-S-ethyl-2,3-dihydrofuran-3-one and4-hydroxy-5-methyl-2-ethyl 2,3-dihydrofuran-3-one 5 1.01 p.p.m. triplet(.II1C Hg 6=1.0-1.5 p.p.m. multipltt /0 I CH:1C

6:1.56 p.p.m. multiplet 0 6:2.70 p.p.m. quartet CH3-2Ize=3.2-4.0 .p.m.multi lier... v H

6:4.19 p p.m. quartet O 6 422 p p.m. quartet H:C(|3\ p.p.m. niultiplet.2

6=5.12-p.p.m. singlet. Br 6=5.31 p.p.m. singlet ?)(:J(3- 5:5.43 p.p.m.singlet 0 g 0 The above-prepared bromo compound was treated with 9.8 g(0.1 mole) of potassium acetate in 100 ml of acetone as described above.After working up, the residue was stirred with 200 ml 0.25 N HClsolution at C for 1 hour. The aqueous reaction mixture was continuouslyextracted with ether for 18 hours. The ether extract was dried andevaporated and the residue was found tocontain a 217:3 mixture of thetitle compounds. From this. mixture 4-acetoxy-2-methyl-S-ethyl-2,3-dihydrofuran-3-one could be isolated by preparativegas'chromatography'. Mass-spectrum data: m/e 184 (5), 142(83), 127(2.5), 99 (3), (20), 57 43 (53). Infrared absorption characteristics (inCC1 1784, 1720, 1640, 1195 cm.

A 70/30 mixture of 4-hydroxy-2-methyl-S-ethyl-Z,3- dihydrofuran-3-oneand 4-hydroxy-2-ethyl-5-methyl- 2,3-dihydrofuran-3-one could be isolatedby distillation (yield 41%, b.p. 65/0.01 mm Hg). The mass-spectrum ofthis mixture showed the peaks at m/e 142 (66), 127 (10), 99 (18), 71(42), 57 (97), 43 (100).

EXAMPLE 31 Preparation of 4-hydroxy-2,5-dimethyl-2,3-dihydrofuran-3-oneTo a mixture of 118 g (1 mole) of ethyllactate and 1.0 g of dry HCl wasadded in the course of 1 hour at 30C 64 g (1.1 mol) of methylvinylether. The mixture was then stirred for 30 minutes and distilled througha 18.8 g of the hexanedione thus prepared was treated with 17.8 g (0.1mole) of N-bromo succinimide in 100 ml of tetrachloromethane. Afterevaporating off the solvent the bromocompound was treated with 19.6 g(0.2 mole) ofpotassium acetate in 200 ml of acetone and the mixture wasstirred for 10 minutes at 55-58C. After this stirring period the mixturewas filtered and the filtrate evaporated under reduced pressure. Theresidue was dissolved in 200 m1 0.25 N aqueous HCl solution and stirredat 80C for 45 minutes. From the aqueous solution4-hydroxy-2,5-dimethyl-2,3- dihydroturan-3one was isolated in the usualway, yield 3.3 g 26% (calculated on 2-(a1phamethoxyethoxy)-3,5-hexanedione) with m.p. 7981C. 1

EXAMPLE 32 Preparation of '4-hydroxy-2,5-dimethyl-2,3-dihydrofuran-3-one (24.4 g 0.42moles) was then'addedand the reaction mixture was refluxed for 30 minutes. After working up2-tert-butyloxy-3,S-hexanedione was-isolated by destillation, bp. 60-61Cat 2.5 mm Hg, n =1.4539.

18.6 g (0.1 mole) of 2-tert-buty1oxy-3,5 hexanedione was brominated with17.8 g (0.1 mole) of N.bromosuccinimide according to the proceduredescribed aboveand the resulting 4-bromo-2-tert-butyloxy-3,5-hexanedione was treated with 19.6 g (0.2 mole) of potassium acetate in200 ml of acetone; After working up, the residue was stirred with 400m10.25 N HCl solutio at 80C for 45 minutes.

Extraction of the aqueous acidic solution with ether and crystallisationof the evaporated ether extract afforded 6.0 g 47% (calculated on2-tert.-butyloxy-3,5-

EXAMPLE 33 Preparation of 4-hydroxy-2 ,5-dimethyl-2,3-dihydrofuran-3-oneTo a stirred mixture of 1 18 g 1.0 mole) of ethyllactate and 0.5 g ofKHSO, was added in 20 minutes at 40C 79 g (1.1 mole) of ethylvinylether.Stirring was continued for another 30 min. and the reaction mixture wasdestilled through a 30 cm Vigreux-columnflhe product with hp. 68C at 4mm Hg was collected, which proved to be pure 2-0-(alphaethoxyethyl)-ethyllactate. Yield 180 g 95%, n 1.4098. 58 g (1.0 mole) of acetone wasacylated with 152 g (0.8 mole) of the above prepared protected lacticester in 100 ml of dry toluene in'the presence of 40 g (1.0

mole) of sodium m ethoxide The reaction mixture was 8' V To a stirredmixture. of 50.5 g (0.25 mole) of the above prepared hexanedione, 120mlof dimethylform am'ide and 58.8 g. (0.6 mole) of potassium acetate at2025C, was added in 1 hour 410 g (0.255 mole) of bromine. After stirringfor 1 hour, the reaction mixture was poured into 200 ml of ice-water,and the resulting mixture was extracted five times with 100 ml ofnpentane. The combined pentane extract was washed with 50 m1 of water,evaporated and the resulting residue was dissolved in 150 ml of a 3%aqueous oxalic acid solution and refluxed for 1 hour. From this solution4-hydroxy-2,5-dimethyl-2,3-dihydrofuran-3-one was isolated in a manneras described earlier. Yield: 12.9 g= 41% (calculated on 2-O-(a1phaethoxy ethyl)- 3,5'-hexanedione) with mp. '7880C.

EXAMPLE 34 Preparation of 4-hydroxy-2,5-dimethyl-2,3-dihydrofuran-3-oneA mixture of 29.2 g (0.2 mol) of alpha-ethoxyethylpropionatelpreparedaccording to the method described by A. A. Petrov, et a1. Zhur ObshekeiKhim; 23, 737 (1953)] and 23,2 g (0.4 mol) of acetone was added in thecourse of 30 minutes at 2025C to a mixture of 16 g (0.4 mol) ofsodiummethoxide and ml of dry pentane whilst stirring. Stirring was continuedafter completing the addition foranother 15 minutes at 20C.

After working up the reaction mixture 2 ethoxy-3,5- hexanedione-wasisolated. by distillation (b.p. 40C at 0,1 mm Hg. a 1.4553). Infraredabsorption characteristics: maxima at (liquid) 2980, 2940, 2880, 1735,1715, 1615, 1450, 1370, 1323, 1240, 1170, 1115, 1070, 1030, 945, 885 and800 cm.

Toastirred mixture of 15.8g(0.1 mol) of the above prepared hexanedione,ml of dimethylformamide and 294g (0.3 mole ofpotassiumacetate at 2025C,was added in 30 minutes 16.0 g (0.1 mole) of bromine. After stirring foran hour at room temperature, the reaction mixture was pouredinto ml ofice-water and the resulting mixture was extracted 5 times with 50 m1pentane portions. The combined pentane extracts were washed with 30 mlof water and evaporated. From the resulting residue 16.2 g 75% of2-ethoxy-4-acetoxy- 3,5-hexanedione was isolated by distillation (b.p.62 at 0.1 mm Hg, n 1.4408). Infrared absorption characteristics: maximaat (0C1, solution) 2980, 2940,. 2880, 1760, 1735, 1728,1450, 1375, 1232,1113 and 904 cm. The mass spectrum showed peaks at m/e 42, 43, 44, 45,45, 57, 73, 74, 85, 86, 1 16, 128. NMR (CCl, solution withtrimethylsilane as internal standard).

.17 ppm triplet .19 ppm triplet ppm doublet ppm quartet ppm quartet ppmsinglet ppm doublet 0 ppm singlet 16.2 g (0.075 mole) of the aboveprepared 2-ethoxy- 4-acetoxy-3,5-hexanedione was added in the course of15 minutes at -5C to 50ml of concentrated sulphuric acid, which wasvigorously stirred. Stirring'was continued for another minutes at 0-50Cand then the reaction mixture was poured on 150 g of crushed ice. Theaqueous solution so obtained was continuously extracted with ether for12 hours. The ether extract was dried and evaporated and the residue wascrystallized from ether. After standing overnight in the refrigeratorthe crystals were collected by filtration (6.45 g. 50% yield calculatedon 2-ethoxy-3,5-hexanedione), mp. 77-78C, and proved to be pure4-hdyroxy-2,5- dimethyl-2,3-dihydrofuran-3-one, when examined by GasLiquid Chromatography.

EXAMPLE Preparation of 4hydroxy-2.5-dimethy1-2,3-dihydrofuran-3-one 20.2g (0.1 mole) of 2-(alpha-ethoxyethoxy)-3.5- hexanedione was brominatedwith 17.8 g (0.1 mole) of N-bromosuccinimide according to the proceduredescribed earlier. The resulting4-bromo-2-(alphaethoxyethoxy)-3,S-hexanedione showed infrared absorptioncharacteristic maxima in CCL, at: 2980, 2940, 2900, 1750, 1725, 1450,1390, 1360, 1100 1082, 950, and 856 cm. NMR in CCl, (withtrimethylsilane as an internal standard).

5= 1.17 ppm triplet 8= 2.38 ppm singlet 1.30 ppm doublet 2.40 ppmsinglet 1.40 ppm doublet 2.50 ppm singlet 1.50 ppm doublet 2.55 ppmsinglet 8= 3.55 ppm multiplet 8 5 .20 ppm singlet 4.20 ppm quartet 5.26ppm singlet 4.75 ppm quartet 5.37 ppm singlet 5.50 ppm singlet EXAMPLE36 Preparation of 4-hydroxy-2,5-dimethyl-2,3-dihdyrofuran-3-one Amixture of 20.8 g (0.1 'mole) alpha-benzyloxyethylp'ropionate [preparedaccording to the method ,described by K. Mislow et al. J.Am.Chem.Soc.84, 1940-4 (1962)] and 11,6 g (0.2 mol) of acetone was added in thecourse of 30 minutes at l0l5C (icebath) to a stirring mixture 8.0 g (0.2mol) of sodiummethoxide and 40 ml of dry pentane. Stirring was continuedafter completing the addition for another 30 minutes at 5C. Afterworking up the reaction mixture 2-benzyloxy-3,5-hexanedione was isolatedby destillation (b.p 92C at 0.05 mm Hg n,, 1.5252). Infrared absorptioncharacteristics: maxima at (CCl, solution). 3090, 3070, 3040, 2990.2940. 2870, 1610 (S, br.),

8== 1.40 ppm doublet 8= 4.55 ppm doublet 2.05 ppm singlet 5.85 ppmsinglet 8 ppm quartet 7.27 ppm singlet 3.8 4.45 ppm doublet 17.6 g (0.08mol) of the above prepared 2-benzyloxy-3,5-hexanedione was dissolved inml of dimethyl formamide and to thissolution was added 24 g (0.24 mol)of potassiumacetate. To the mixture so obtained was added in the courseof 1 hour at 20-22C 12,8 g (0.08 mol) of bromine. After stirring for onehour at the same temperature, the reaction mixture was poured into 160ml of water and this solution was extracted five times with 40 mlpentane portionsrThe combined pentane extracts were washed with water,dried and evaporated. The resulting residue proved to be pure2-benzyloxy-4-acetoxy-3,5-hexanedione.

infrared absorption characteristics maxima at (CCl, solution) 3090,3060, 3040, 2990, 2940, 2880, 1765, 1750, 1730, 1610, 1502, 1458, 1373,1361, 1230, 1208, 1165, 1110, 1030, 982, 903 and 696 cm. The massspectrum showed peaks at: m/e 43,51, 65, 77, 91, 101,135,146,164, 206,235. NMR (CCL, solution with trimethylsilane as an internal standard) 81.33 ppm doublet 8 4.06 ppm quartet 1.35 ppm doublet 4.15 ppm quartet2.02 ppm singlet 4.40 ppm quartet 2.15 ppm singlet 4.50 ppm singlet 2.18ppm singlet 5.70 ppm singlet 5.85 ppm singlet 7.30 ppm singlet 13.9 g(0.05 mole) of the above prepared 2- benzyloxy-4-acetoxy-3,S-hexanedionewas added at 0C to 28 ml of concentrated sulphuric acid, which wasvigorously stirred. After a 10 minutes reaction period the mixture waspoured on to g of crushed ice. The title compound was isolated from theaqueous solution in the usual way. Yield 2,6 g 41.0% (calculated on2-benzyloxy-4-acetoxy3,5-hexanedione) with mp. 7880C.

EXAMPLE 37 0.1 g of 4-acetoxy-Z-tetrahydropyranyloxy-B,5- hexanedione(prepared according to Ex. 3) was added to a mixture of 10 g ofhydrogenated vegetable fat and 0.1 ml of water and the mixture washeated to C for 5 minutes. After cooling the fat thus obtained wascompared with a sample to which no 4'acetoxy-2-tetrahydropyranyloxy-3,S-hexanedione had been added. The heated productto which the diketone had been added was generally preferred because ofits flavour which was reminiscent of 2,5-dimethyl-4- hydroxyfuran-3-one.

What is claimed is: i

1. A method for the preparation of a substituted 2,3- dihydrofuran-3-oneof the structure R3ZC =o R1 4211-11 or a tautomeric structure thereof inwhich R, R and R and Z represent groups indicated above and R representsan alcohol protecting group resistant to alkali but removable under'acidreaction conditions selected from the class consisting of a C--C alkylgroup, 2- tetrahydrofuranyl group, 2-.tetrahydropyranyl group, a

methoxyethyl or ethoxyethyl group, or an aor B- unsaturated groupselected from an allyl, benzyl, or a metaor para-methoxy phenyl.

2. A method according to claim 1 in which R and R each represent analkyl group. i

3. A method according to claim 1 in which R represents an alkyl groupcontaining l'-4 carbon atoms.

4. A method according to claim 2 in which R represents an alkyl groupcontaining 1-4 carbon atoms.

5. A method according to claim 1, in which the acid is an optionallysubstituted C -C mono-, di-, or tricarboxylic, or thiocarboxylic acid,an inorganic acid or a so-called aprotic Lewis acid.

6. A method according to claim 1, in which the reaction is carried outat atemperature ranging from 30 to C.

7. A method according to claim 1, in which the reaction time rangesbetween several minutes and a few hours.

1. A METHOD FOR THE PREPARATION OF A SUBSTITUTED 2,3DIHYDROFURAN-3-ONEOF THE STRUCTURE
 2. A method according to claim 1 in which R1 and R2each represent an alkyl group.
 3. A method according to claim 1 in whichR3 represents an alkyl group containing 1-4 carbon atoms.
 4. A methodaccording to claim 2 in which R3 represents an alkyl group containing1-4 carbon atoms.
 5. A method according to claim 1, in which the acid isan optionally substituted C1-C8 mono-, di-, or tricarboxylic, orthiocarboxylic acid, an inorganic acid or a so-called aprotic Lewisacid.
 6. A method according to claim 1, in which the reaction is carriedout at a temperature ranging from -30* to 150*C.
 7. A method accordingto claim 1, in which the reaction time ranges between several minutesand a few hours.